Minimal residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM) and a valid surrogate for progression-free survival (PFS) and overall survival (OS). Recently, MRD negativity was approved as an early clinical endpoint for accelerated drug approval in MM. Nevertheless, there is limited evidence of MRD utility in real-world setting. In this retrospective multicenter study, we report outcomes of 331 newly diagnosed MM patients with MRD evaluation at Day+100 after autologous stem cell transplantation using flow cytometry with a median limit of detection of 0.001%. MRD negativity was reached in 47% of patients and was associated with significantly prolonged median PFS (49.2 months vs. 18.4 months; hazard ratios (HR) = 0.37; p < 0.001) and OS (not reached vs. 74.9 months; HR = 0.50; p = 0.007). Achieving MRD negativity was associated with PFS improvements regardless of age, International Staging System (ISS) stage, lactate dedydrogenase (LDH) level, or cytogenetic risk. Importantly, MRD positive patients benefited from lenalidomide maintenance versus no maintenance (18-months PFS: 81% vs. 46%; HR = 0.24; p = 0.002) while in MRD negative patients such benefit was not observed (p = 0.747). The outcomes of our real-world study recapitulate results from clinical trials including meta-analyses and support the idea that MRD positive patients profit more from lenalidomide maintenance than MRD negative ones.
- MeSH
- autologní transplantace MeSH
- dospělí MeSH
- lenalidomid aplikace a dávkování terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom * diagnóza mortalita terapie patologie MeSH
- prognóza MeSH
- průtoková cytometrie * metody MeSH
- retrospektivní studie MeSH
- reziduální nádor * diagnóza MeSH
- senioři MeSH
- staging nádorů MeSH
- transplantace hematopoetických kmenových buněk metody MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Despite significant advancements in therapy of multiple myeloma (MM) over the past 20 years, most patients experience relapse, necessitating new treatment approaches. This study aims to compare the real-world effectiveness of lenalidomide (LEN)-based triplet therapies, specifically daratumumab (DRD), carfilzomib (KRD), and ixazomib (IRD), in relapsed/refractory multiple myeloma (RRMM).A retrospective registry-based study analyzed 538 RRMM patients undergoing therapy for their first to third relapse. The primary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), with a matching-adjusted indirect comparisons (MAIC) employed to address cohort differences.ORR was highest for DRD at 91.4%, followed by KRD (89.6%) and IRD cohorts (Early-IRD: 79.6%, Late-IRD: 70.8%). Median PFS for DRD was greater at 23.64 months compared to KRD (16.52 months) and IRD groups (Early-IRD: 19.97 months, Late-IRD: 11.57 months). The MAIC confirmed better outcomes for the DRD regimen. High-risk features were not overcome by any of the LEN-based regimens.The findings underscore the superior efficacy of DRD in achieving sustained responses in RRMM patients. The composition of the cohort is a crucial factor, extending beyond selection criteria. This study highlights the importance of real-world evidence in assessing treatment modalities in clinical settings.
- MeSH
- chemorezistence MeSH
- dospělí MeSH
- glycin analogy a deriváty aplikace a dávkování MeSH
- lenalidomid * aplikace a dávkování terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru * farmakoterapie MeSH
- mnohočetný myelom * farmakoterapie mortalita patologie MeSH
- monoklonální protilátky aplikace a dávkování terapeutické užití MeSH
- oligopeptidy aplikace a dávkování MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití MeSH
- registrace MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sloučeniny boru aplikace a dávkování terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Induction therapy followed by CD34+ cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34+ cells using flow cytometry and transcriptomics. Decreased CD34+ cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34+ subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34+ cells from 21 patients showed that adhesion genes are overexpressed in CD34+ cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34+ cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy.
Cíl: Cílem tohoto sdělení je prezentovat velmi zajímavý případ detekce AL amyloidózy myokardu pomocí scintigrafie srdce s 99m Tc-DPD u 73letého pacienta vyšetřovaného pro námahovou dušností a kardiální selhávání. Metodika: UZ srdce zjistilo hypertrofii levé srdeční komory se sníženou systolickou funkci levé srdeční komory. Pacient následně absolvoval koronarografii s normálním nálezem v koronárním řečišti. Bylo vysloveno podezření na amyloidózu myokardu a indikována scintigrafie myokardu s 99m Tc-butedronátem. Aplikovaná aktivita 99m Tc-DPD činila 700 MBq intravenózně. Byla provedena planární scintigrafie a SPECT hrudníku za 3 hodiny po i.v. aplikaci radiofarmaka. Výsledky: Zobrazila se difuzně zvýšená akumulace radiofarmaka v myokardu levé a pravé srdeční komory. Intenzita akumulace RF odpovídala stupni 3 podle Perugini škály. Vyšetření svědčilo pro průkaz amyloidu v myokardu. K diferenciální diagnostice transthyretinové a AL amyloidózy byla provedena imunoelektroforéza bílkovin z krevního séra a moči spolu s vyšetřením na volné lehké řetězce imunoglobulinů. Byla prokázána patologická hladina volných řetězců lambda a detekován paraprotein IgG lambda 6,5 g/l. Byla doplněna endomyokardiální biopsie, která potvrdila AL amyloidó- zu myokardu typu lambda. Byla nasazena biologická léčba daratumumabem v kombinaci s bortezomibem, cyclofosfamidem a dexametazonem, která vedla ke stabilizaci stavu. Závěr: Scintigrafie myokardu s 99m Tc-DPD je vysoce senzitivní metodou pro diagnostiku transthyretinové amyloidózy srdce, může však být falešně pozitivní u AL amyloidózy. U všech pacientů se srdeční amyloidózou je proto třeba vyšetřit přítomnost monoklonální gamapatie pomocí imunoelektroforézy séra a moči spolu s vyšetřením volných řetězců imunoglobulinů. Při abnormálním výsledku těchto testů je třeba verifikovat typ srdeční amyloidózy biopticky.
Aim: To present an interesting case of detection of AL myocardial amyloidosis by cardiac scintigraphy with 99m Tc-DPD in a 73-year-old patient investigated for exertional dyspnea and heart failure. Method: Cardiac ultrasound revealed left ventricular hypertrophy with decreased left ventricular systolic function. The patient subsequently underwent coronary angiography with normal coronary findings. Myocardial amyloidosis was suspected and myocardial scintigraphy with 99m Tc-butedronate was indicated. The administered activity of 99m Tc-DPD was 700 MBq intravenously. Planar scintigraphy and chest SPECT were performed 3 hours after intravenous administration of the radiopharmaceutical. Results: Diffusely increased uptake of 99m Tc- DPD in the myocardium of the left and right ventricles was observed. The intensity of tracer uptake corresponded to Perugini scale grade 3. The examination was suggestive of cardiac amyloidosis. To differentiate transthyretin and AL amyloidosis, we performed immunoelectrophoresis of serum and urinary proteins together with assessment of free immunoglobulin light chains. The analysis revealed marked elevation of free lambda chains and detected paraprotein IgG lambda 6,5 g/L, which confirmed an increased level of free immunoglobulin light chains. An endomyocardial biopsy confirmed the lambda light chaintype of myocardial amyloidosis. A biological therapy, with daratumumab in a combination with bortezomib, cyclophosphamide and dexamethasone, was initiated. Conclusion: Myocardial scintigraphy with 99m Tc-DPD is a highly sensitive method for the diagnosis of transthyretin amyloid cardio- myopathy. However, it can be false positive in AL amyloidosis and monoclonal gammopathy must be evaluated in all subjects with cardiac amyloidosis by means of immunoelectrophoresis of serum and urine together with assess- ment of free immunoglobulin light chains. An abnormal result of these assays requires a bioptic verification of amyloid.
BACKGROUND: Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse. METHODS: In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed. RESULTS: A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group. CONCLUSIONS: Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.).
- MeSH
- bortezomib aplikace a dávkování škodlivé účinky MeSH
- chemorezistence MeSH
- dexamethason * aplikace a dávkování škodlivé účinky MeSH
- doba přežití bez progrese choroby * MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * aplikace a dávkování škodlivé účinky MeSH
- Kaplanův-Meierův odhad MeSH
- lenalidomid aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru diagnóza farmakoterapie mortalita MeSH
- mnohočetný myelom * diagnóza farmakoterapie mortalita MeSH
- oční nemoci chemicky indukované epidemiologie MeSH
- progrese nemoci MeSH
- protokoly protinádorové kombinované chemoterapie * aplikace a dávkování škodlivé účinky MeSH
- recidiva MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thalidomid * aplikace a dávkování škodlivé účinky analogy a deriváty MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.
- MeSH
- antibakteriální látky škodlivé účinky farmakokinetika MeSH
- ceftazidim škodlivé účinky farmakokinetika MeSH
- chromatografie kapalinová MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- mikrobiální testy citlivosti MeSH
- nádory * komplikace farmakoterapie MeSH
- off-label použití léčivého přípravku MeSH
- pseudomonádové infekce * farmakoterapie MeSH
- Pseudomonas aeruginosa MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Although novel therapies improved prognosis of multiple myeloma (MM) patients, clinical outcomes in the multi-refractory population are still poor. PATIENTS AND METHODS: We reviewed data from the Czech Registry of Monoclonal Gammopathies, identified and characterized triple-class exposed (3CE) relapsed/refractory MM patients, treatment patterns after 3CE, assessed overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), explored cohorts with and without triple- and penta-refractoriness. RESULTS: In 83 3CE patients who started subsequent therapies, the median OS was 14.2 months (95% CI, 8.5-19.9), PFS 6.2 months (95% CI, 3.9-8.5), and TTNT 7.2 months (95% CI, 4.6-9.8). Triple- and penta-class refractory patients had a significantly worse prognosis in all outcomes. Their life expectancy was shorter, the disease progression started earlier, and the TTNT was shorter, which increased likelihood of becoming refractory to more therapies. Time-to-event results from the first index date and all index dates analyses were very similar. CONCLUSION: Similar to previous studies from the US and Europe, our results show a high disease burden. Introduction of novel therapies, such as CAR-T cells, new bispecific and trispecific monoclonal antibodies, and other drugs, is expected to bring significant benefits to these patients.
- MeSH
- doba přežití bez progrese choroby MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- registrace MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
PURPOSE: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. METHODS: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. RESULTS: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. CONCLUSION: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.
Mnohočetný myelom je krevní nádorové onemocnění charakterizované proliferací klonálních plasmatických buněk v kostní dřeni a přítomností paraproteinu v séru a/nebo moči. V posledních letech se pro diagnostiku i pro celý průběh léčby dostává do popředí celotělová zobrazovací metoda pozitronová emisní tomografie (PET) kombinovaná s výpočetní tomografií (PET/CT). Její výhodou je zachycení metabolicky aktivních charakteristických ložisek a dobrá detekce extramedulárních i paramedulárních lézí. Následující text shrnuje společné stanovisko odborníků České společnosti nukleární medicíny ČLS JEP z. s. (ČSNM ČLS JEP) a České myelomové skupiny (CMG) jak k provedení vyšetření PET/CT, tak k jeho hodnocení a reportování. Cílem je sjednotit metodiku vyšetření PET/CT napříč pracovišti v ČR, která bude srozumitelná a jednoznačná.
Multiple myeloma is a blood cancer characterized by proliferation of clonal plasma cells in the bone marrow and the presence of paraprotein in the serum and/or urine. In recent years, whole-body positron emission tomography (PET) imaging combined with computed tomography (PET/CT) has become a preferred imaging technique for diagnosis and treatment. It has the benefit of detecting metabolically active characteristic focuses and good detection of extramedullary and paramedullary lesions. The following text presents the collective opinion of the representatives of the Czech Society of Nuclear Medicine ČLS JEP z.s. (CSNM ČLS JEP) and the Czech Myeloma Group (CMG) on PET/CT as well as on its evaluation and reporting. The aim is to standardize the methodology of PET/CT examination across the Czech Republic, which will be clear and simple to understand.
- Klíčová slova
- extramedulární ložiska, paramedulární ložiska,
- MeSH
- kritéria léčebné odpovědi MeSH
- lidé MeSH
- mnohočetný myelom * diagnostické zobrazování MeSH
- PET/CT metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
